Substituted l



SU STIT TED 2,3-DIPHENYL 1,4rDIOX-TETRA- Y ROPHIH A NES A PRQS ESS F 15 PREPARING THEM many No Drawing. Application August 2, 1955 Serial No; 526,072

we W st n rma au s 7,

7- Claims. (Cl. 260-250) The Pre en nve ion e tes o et a y oph h a e o t e ormu a whe e It represents a free, an alkylated or an acylated '11 roxyl'or'a ino' group, as well'as to'their salts and a I pr"paring?thejabovefiientionedcompounds, 'Sub'st showing. strong najrcoue' fict are o an extraordinary therapeutic importance, the number of tfi, e'ifective" substanc e'groups, however; being small. For many years the barbiturates have predominated, although they are rather dangerous and their administration must be carefully conti'olled.

Now we have found that 2,3-diphenyl-1,4-dioxo-tetrahydrophthalazines substituted in the phthalic acid radical show a strong narcotic effect. The cOnip'oufidsare oh tained by condensing phthalic chlorides or phthalic sit hydrides once or several times substituted by mire-grams, hydroxy-groups or acylamino groups, in an anhydrous medium and in the presence of tertiary amines, by means of hydrazobenzene. According to the inventionfnitro groups eventually present in the condensation products are reduced to amino groups. Acylarnino groups eventually present are likewise hydrolized to amino groups. Amino alkyl radicals can be introduced into the amino groups and/or into hydroxy groups eventually present. The amino groups and/or hydroxy groups can also be acylated' and, in this manner, compounds are obtained which are readily soluble in water or oil and well adapted for parenteral or oral application.

' There. enter into consideration, for instance, the following substituted phthalic chlorides or phthalic anhydrides: 3- nitrqor A-nitro-phthalic chloride, 4-hydroxyor 3 -hydroXy phthalic' anhydride.

t The condensation with hydrazobenzene is carried out in the presence of'tertiary amines, such as pyridine, or dimethylanilin e. When phthalic chlorides are used, these amines simultaneously serve as hydrogen halide acceptor.

It is of advantage to carry out the reaction in inert solvents or distributingagents such as benzene, or toluene. If need be, the tertiary amines can also be used as solvents or distributing agents. The reaction can be performed at theordinary or at'an elevated temperature.

In order to obtain the condensation products, the reaction'niirrture, eventually after concentration under re.- duced pressure, is acidified,"advantageously by means of mineral acids. In many cases the condensation products a e; therebyobt ind in a crystallinestructure. "The reduction of effected means or hydrogen in'the presence of Rai1y United States Patent 0 iia y'pre ent n tr r up s silitably I 2,874,156 Wa t dv Feb: 17: 1 5*? nickel; it can, however, also be efie'cted according to other usual methods, for his" rice by means ofti"'and hydrochloric acid. The hyd sis of theconden ation products containing acyl-aniirio group's'can be'cai'i'i d out 5 in the usual rriannefQ The phthalazi'nde'rivative's thusobtained; 1. e."the amino orhydrdiyafi diphenylfl,4 dioxo-tetrahydrophthalazines "are" yellowish substances sparingly solublejn water. They canbe transformed into water soluble substances by basic alkylat'io'n, for instance bymeansofdietliylamino-ethyhchloride, pipei idino-ethyl-chloride,"morpholino-ethyl-chlor'ide; niethyl amih'oethyl-chloride.

"In order to obtain the *a'cyl derivatives able in water it is possible to react the phthalazihes',eventually in the form of thjeir alkali 'rnet'al compounds," with acid halides containinga tertiary 61; a quaternary nitrogenatomj'or' their salts, with eventual quaternation of a tertiary 'ititro gen atom present in thecompounds obtained. The acyla tion can likewise be carried oirti'n twostage's by reaction with a halogenacyll'ialide and a subsequent reaction with a secondary or a tertiary amine" and'by converting the basic esters obtained intdsaltfwith 'ino'r'ga'nic'or organic acids, such as hydrochloric acid, sulfuric a'cid,nitric"acid, acetic acid, lactic acid, or maleic acid. f

Acyl derivatives soluble'in oil can be prepared by reacting substituted phthalazines, eventuallyin' the form of their alkali metal compounds, with'saturated or unsatu'rated, non-substituted fatty acid halides.

As starting materials "there are-usedon the one hand, the attire-mentioned" 'ZZB-diphhyl l:, 4-dioxo tefrahydro phthalazines containing hydr'oriybr amino" groups, on the other hand acidhali'des, "which; forinstancejcan bepre pared as follows:

It is possible, for instance, ,to convert betaine hydrochloride by means of thionyl chloride into N-chloro-- betainyl-chloride, according to U. S. Patent lfIp. 2,352 6 chloridesofqiiaifinarycarb' can 'beprodiiccd, accordingtc' I, Chi'hl 'Socl, L6 (1947), page 179, by quaternationof ethylene chlorw hydrine with triethyl amine and reaction of the quaternary alcohol obtainedwith"phosgenel Ako Chem. Soc. (1953), pag 63fi4 fp'yri chlorides can be obtained, for inst pyridine-carboxylic acid salts," for t V salt'of nicotinic-acidw ith oi lchlor'df" oam nrter Nit-6229a; the typ o th d a ky amino chloride can be, canine ff g p 'ydro'chloridebynie nsfo, th yl' chlo do. to r S C- 21 2. 1 32?? 2 86 1/, Y, chloride can a uy e cha ns by ea n acrylic a with benzoyl chloride; oleic "an chloride and" fstca'ric acid chloride are readily accessible froin'the carbg licj acids bythe action'ofthionyl 'd'el Ther will be nientie e to; astance he (fo lowin acidhalides which enter intbco idera'tio'nes' starting materials for the processaccordi to the invention:

N- h o tainy h 1; br gesst l bromi e, h oa y hlorid wore-f rmic a id-(fir i hyfor instance, in the fol 2,3! 5

p'ratiirejas well as at a Farticula rly when crystall r 9 isf advisablle to operate"'1n the presenceof solven and; distribti'tifig age fits fin ins taboo iiibrnatic hydrbciirb diltl such as benzene, toluene, xylene, or halogenated hydrocarbons such as chlorobenzene, methylene chloride, or chloroform. It is advantageous also to add a tertiary base such as pyridine or dimethylaniline as acid binding agent. In the last-mentioned case the presence of a further solvent or distributing agent is superfluous. The acylation can also be carried out in sucha way as to react the alkali metal compounds of the phthalazines with the above-named acid halides in the presence or absence of one of the afore-mentioned inert solvents or distributing agents.

Acid halides which, in the alkyl chain, carry a quaternary nitrogen atom, can be used already as starting substances. However, it is also possible to carry out the reaction with monohalo acid halides and to convert, by means of trialkylamines, the halogenated esters obtained into quaternary ammonium compounds or, by means of dialkylamines, into basic esters with a tertiary nitrogen atom. Finally, the reaction can also be carried out by means of tertiary aminocarboxylic acid halides, eventually in the form of the corresponding salts, and the basic esters obtained can eventually be quaternized by means of esters of low aliphatic alcohols and strong mineral acids. The quaternation can be carried out at normal temperature as well as at a slightly'elevated temperature and in the presence or absence of one of the inert solvents and distributing agents already mentioned or a surplus of the quaternation reagent which, in such a case, simultaneously serves as a solvent.

The compounds obtainable according to the process of the present invention are to be used as medicaments, particularly asorally and parenterally applicable narcotics. In contradistinctiou to the barbiturates, the substances are characterized by a stronger narcotic effect,

(1927), page 73). In comparison with the known products, which, according to what we found out, also possess sedative effects, the compounds obtained according to the present invention, as far as they contain aminoor hydroxy-groups in the 'phthalic acid radical, show a broader therapeutic field of application. After the basic alkylation or acylation the compounds obtained according to the invention are, as salts, soluble in water or oil and are of a good therapeutic efiiciency.

The following examples serve to illustrate the invention but they are not intended to limit it thereto:

EXAMPLE 1 6-mnino-2,3- diphenyl-1,4-diox0-tetrahydr0phthblazine 200 grams of .4-nitrophthalyl-chloride (0.806 'mol) are slowly added dropwise, while stirring, to a suspension of 147 grams of hydrazobenzenev (0.806- mol) in 300 cc. 'of dry dimethylaniline. During the reaction the mixture is diluted by 1.2 liters of absolute benzene, so that it can still be stirred. The temperature rises to 60 C.- 70 C. Finally, the mixture is-still heated for 2 hours to 100 C. (internal temperature). After cooling the reaction mixture is stirred into a mixture of 500 cc. of concentrated hydrochloric acid and 3 liters of water. The amorphous precipitate is filtered with suction, washed with water and triturated with ether, whereby crystallization sets in. Yield: 200 grams of 6-nitro-2,3-diphenyl- 1,4-dioxo-tetrahydrophth'alazine (69% of the theoretical yield); melting point 189l9l C.

The same compound can equally be prepared as fol-' lows:'92 grams of hydrazobenzene (0.5 mol) are stirred into a solution of 96.5 grams of'4-nitrophthalic anhydride (0.5 mol) in 350 cc. of absolute pyridine. The

as this results from the following table: mixture is heated for 3 hours to an internal temperature Substance Animal. Efiective dose, Kg.

5(B-bromoallyl)-5 secondary butyl-barbiturate gfgggx gg intravenously 6-arnino-2,3-diphenyl-l,4-dioxotetrahydrophthalazine Rabbit" 2 milligrams intravenously. 5-amino-2,3-diphenyl-l,4-dioxo-tetrahydrophthalazine Mouse" 10 milligrams intravenously. 6-hydr0xy-2,3-diphenyl-1,4-dioxotetrahydrophthalazina g :6 8: 32333833? fi-hydroxy-2,3-diphenyl-1,4dloxotetrahydrophthalazino figggf 2 gff mtravemusly' '0 7.5 m lligrams intravenously. 5 dimethylamino acetoxy-2,3 diphenyl 1 4 -dioxo-tetrahydro- {fi abblt 1.75 milligrams/minute when permanently infused. phthalazmechloromethylate. 10 milligrams intravenously 5 nicotinoyloxy 2,3 diphenyl 1,4 dioxo tetrahydrophthal- Rabbit-- Do.

2a3Z1;efi)r0DilO1e21dyi18t8.tBtr h d mm 1 i H )1 Dog 15 milligrams intravenously.

eny- 0x0- ayrop aazny-5 ifidieiihylamineethyH-carbonate ethyl-nitrate 20 milligrams intravenously Moreover, when compared with the barbiturate, taken for comparison, the depth of the narcosis is reduced. According to the dose administered, the duration of the narcosis varies between 15 and 30 minutes.

, As regards the acyl derivatives soluble in water, those deriving from S-hydroxyor 6-hydroxy-2,3-diphenyl-1,4- dioXo-tetrahydrophthalazine are especially readily and rapidly cleavable at'the phenol-ester linkage already under physiological conditions, whereby the 2,3-diphenyl- 1,4-dioxo -tetrahydrophthalazines containing hydroxy groups are set free in a highly dispersed and easily reabsorbing manner. In the case of parenteral application, especially when halogen alkylates of the 5- or 6-dialkylamino-acetoxy 2,3 diphenyl 1,4 dioxo-tetrahydrophthalazine are used during operations, a special advantage is represented by the fact that they are of a strong curare effect which diminishes in the same extent as the hydrolytic cleavage progresses. Thus, it is possible by means of a permanent infusion continuously to control the degree of the curarization at the sleeping animal.

It is already known to condense phthalic chloride in the presence of dimethylaniline by means of hydrazobenzene or hydrazotoluene, whereby dioxotetrahydrophthalazines .are likewise obtained (Angew. Chemie 40 of 100 C. Then, the major-part of the pyridine is filtered with suction under reduced pressure. The oily residue is poured into 2 N-hydrochloric acid. The precipitate is repeatedly washed by means of 2 N-hydrochloric acid, dried and recrystallized from methanol; melting point 189-l9l C. 200 grams of 6-nitro-2,3- diphenyl-1,4-dioxo-tetrahydrophthalazine are suspended in 1.5 liters of methanol and hydrogenated in the pres ence of Raney nickel. The theoretical amount of hydrogenis thereby absorbed. After separation of the catalyst, the mixture is evaporated and recrystallized from ethyl acetate. -6-amino-2,3-diphenyl-1,4-dioxo-tetrahydrophthalazine is obtained; melting point 238 240" C.

EXAMPLE 2 5 -amin0-2,3-a'ipizenyl-l ,4 -dioxo-tetrahydrophthalazine 1.7 liters of absolute benzene are filled into a threenecked flask of 6 liters capacity. Then are simultaneously added, while vigorously stir-ring, a suspensionv of 490 0 grams of hydrazobenzene (2.69 mol) in l liter'of dry 4 ture is maintained at 4045 C. by cooling.

is pouredinto 2 N-hydrochloric acid, theresulting precipi-v tate is strongly filtered with suction and recrystallized from glacial acetic acid. Yield: 170- grams of'5 nitro- 2,3-diphenyl-l,4-dioxo-tetrahydrophathalazine (81% of the theoreticalyield); melting point 250 254" C.

240 grams of the nitro compound are suspended in 1.4 liters of methanolhydrogenated in the presence of Raney nickel. -W-hen the absorption of hydrogen is finished, the reaction product crystallized out is again brought into dissolution by adding methanol. It is filtered with suction from the catalyst, concentrated and caused to crystallize. out. S-amino-2,3-diphenyl-1,4- dioxotetrahydrophthalazine is obtained melting at 190- EXAMPLE 3.

'5-(fi-diethylam ino-ethylamina)-2;3-diphenyl-1',4-diox0- tetrahydrophthalazine EXAMPLE 4 6-l 1yar0.ty- 2,3-dipheny-l-l ,4-dz'oxo-tetrahydroph thalazine 16.4 grams of 4-hydroxy-phthalic acid anhydride (0.1 mol) and 18.4 grams of hyd'razobenzene (0.1 mol) are dissolved in 280 cc. of absolute pyridine and heated to 110 C. (internal temperature) under reflux for 10 hours. The mass is then poured into 2 Isl-hydrochloric acid. The precipitate set free'is filtered with suction, dried and recrystallized from methanol; melting point 260-270 C. After a second-crystallization the melting point reaches EXAMPLE 5 6-(fl-diethylamino-erhoxy)-2,S-diphenyLIA-(Harm tetrahydrophthalazine a 2.9 cc. of an absolutealcoholic 0.9 3 N-sodiurn ethylate solution are dropwise introduced, while stirring, into a suspension of 900 milligrams of 6-hydroxy-2,3-diphenyl- 1,4-dioxo-tetrahydrophthalazine (obtained according to the process of Example 4) of a melting point of 260- 270 C. (0.00272 mol) in 40 cc. of absolute toluene. After adding 0.51 gram of diethylaminoethyl chloride in an absolute alcoholic solution of strength (0.00378 mol) the mass is heated for 8 hours underrefiux, while stirring, on the oil bath (temperature of the bath 100 C.). Then it is evaporated under reduced pressure,taken up iii-water and ether and shaken out with 1 N-hydrochloric acid. The acid extracts are rendered alkaline by means of potassium carbonate and then shaken out with ether. The ether solution of the base is washed with water, dried with sodium sulfate and concentrated by vaporization. After crystallizing twicejfroma mixture of benzene and petroleum ether the residue melts at 120.-121 C.

. EXAMPLE 6 5-hydr0xy-2,3-diphenyl-1 ,4-dioxo-tetrahydrophtlzalazine 16.4 grams of 3-hydroxy-phthalic anhydride (0.111101) and 18.4 grams of hydrazobenzene (0.1 mol) are dis solved in 100 cc. of absolute pyridine and heated for 7 hours under refluxto 100 C. (internal temperature). Then themass is evaporated under reduced pressure. The residue is washed with dilute hydrochloric acid and recrystallized from methanol. Melting point 188'1-. 1 89* C.

k EXAMPLE 7 S-dimethylaminoflcetaxy-Zfidiphenyl-I ,4-dioxoa tetrahydrophthalazine ch lqromethylate 1 grams or 5.-hyd o.xy-2.,3- pheny -l.4-dio ous hydrophthalazine. (0.0.744 mol). are dissolved in 124 cc. of absolute; pyridine, and 20 grams of; N-chloro-.bet ainyl-. chloride (0.116 mol) pulverized in the. absence of mois-v ture are rapidly added while vigorously stirring. The temperature rises to 2830 C. The mass is; stirred for 8 hours inthe absence. of moisture atroom temperature, and the Py dine is distilled oif at an essentially reduced pressure at a bath temperature of 30 -.-35 C. The, residue from distillation'is dissolved in 500 cc. of dry methylene chloride agitated with 10 grams of, animal charcoal, filtered, concentrated to 250cc. and, precipb tated with 750. cc. of absolute benzene. The solution is decanted from the dark brown, viscous; precipitate, which, on, standing for a prolonged time, completely crystallizes. It is dissolved in the hot in 600 cc. of isopropyl alcohol, 10 grams of animal charcoal are added, the mass is shaken' for some minutes, filtered and concentrated to -150 cc. under reduced pressure. 24. grams of a quaternary salt are crystallized out which can be obtained in a pure state when crystallized repeatedly from isopropyl alcohol. Yield: 22 grams. After the evaporation and the washing with a little methanol 20 cc.), the methylene-chloride-benzene mother liquors obtained during the above decantation yield again 4 grams of S-hydroxy 2,3 diphenyl 1,4 dioxo tetrahydrophthalazine in pure state. The yield, referring to reacted 5'-hydroxy- 2,3-diphenyl-l,4-dioxo-tetrahydro-phthalazine, amounts to 76 of the theoretical yield.

Sometimes the quaternary salt already crystallizes from the reaction mixture. After a reaction period of 8 hours, itis advisable to filter the crystallization product with suction, to purify it in the manner described above by means of methylene chloride and animal charcoal and by crystallization from isopropyl alcohol. The resulting pyridine mother liquors are suitably worked upin order to obtain 5-hydroxy-2,3-diphenyl-1,4-dioxo-tetrahydrophthalazine by evaporation under reduced pressure, taken up in water and addition of a sodium carbonate solution until a strong alkaline reaction is produced. The aqueous alkaline suspensionis allowed to stand for 20 minutes, then acidified and filtered with suction. After washing with 20 cc. of methanol the phthalazinephenol used as startingmaterial is recovered in the pure state.

In the air the quaternary salt rapidly absorbs water of crystallization. According to the conditions of prevailing atmospheric moisture, the water content varies between 2.5 and 3 mols of water of crystallization. At a relative humidity of 50% it amounts to 2% mols. The substance decomposes at 163 165 C. with evolution of gas.

AMPLE 8 5 -diethylaminaacetoxy-2,3-diphenyl-1 ,4-di0x0- tetrahydmphthalazineabromoethylate A suspension of 51.4 grams of the sodium salt of 5- hydroxy-2,6-diphenyl-1,4a dioxo tetrahydrophthalazine (0.146 mol) is added while stirring to a solution of 29.5 grams (0.146 mol) of bromo-acetal-bromide' in 300 cc. of absolute toluene. Thereby a moderate heating occurs. Subsequently the mixture is heated under reflux for 1 hour and, in the hot'state, filtered with suction from the sodium chloride precipitated. During the coolingof the reaction mixture 26 grams of bromo-acetic-acid ester crystallize out, having a melting point of 189 'C. After concentration of the mother liquors a further 18.4 grams of the same melting point are obtained (68% of the theoretical yield).

5 grams of the bromo=acetyl-derivative are heatedin the 30 cc. of absolute triethylamine. Then the triethylamino is removed by distillation and the reaction product is dried in the desiccator over sulfuric acid. The residue is triturated by means of 200 cc. of water. The suspension is rapidly sucked through a filter. The filtrate is submitted to lyophilization. The dry residue is dissolved in the cold in acetone. The solution is filtered, concentrated under reduced pressure and allowed to stand for crystallization. A crystallized quaternary salt is obtained having a decomposition point of 166-168 C. (evolution of gas).

The sodium salt of the 5-hydroxy-2,3-diphenyl-l,4- dioxo-tetrahydrophthalazine used as starting material is prepared as follows: 33.03 grams of the hydroxy-compound A mol) are dissolved in a mixture of 200 cc. of absolute methanol and 100 cc. 1 N-absolute methylalcoholie sodium methylate solution and evaporated nearly to dryness under reduced pressure, at a temperature of the water bath of 40-50 C. The residue is suspended in 200 cc. of absolute toluene, and the toluene is distilled off on the water bath at 40-50" C. in the vacuum. Finally, the salt residue is dried at 56 C. under reduced pressure. The sodium compound is sensitive against moisture and carbonic acid of the air. The yield is quantitative.

The sodium salt of the 6-hydroxy derivative is obtained in an analogous manner.

EXAMPLE 9 [2,3-diphenyl-1 ,4-di0x0-tetrahydrophlhalazinyll [fl-diethylaminoethyl]-carbonate-ethylnitrate 105.6 grams of the sodium salt of 5-hydroxy-2,3-diphenyl-1,4-dioxo-tetrahydrophthalazine (0.3 mol) are suspended in 700 cc. of dry methylene chloride. While stirring, a solution of 73.2 grams (0.3 mol) of chloroformic acid-(,B-diethylaminoethyl)-ester chloroethylate in 500 cc. of dry methylene chloride is added, whereby the temperature rises by 10 C. and the suspension be comes nearly clear. After stirring for several hours, the mass is filtered with suction, and the filtrate is concentrated by evaporation. The crystallized residue is extracted twice with 500 cc. of water each time and sucked through a filter. The remaining insoluble portions consist of pure 5-hydroxy-2,3-diphenyl-l,4-dioxotetrahydrophthalazine (74 grams). In order to split ofi the sparingly soluble iodide, the filtrate is diluted by means of a solution of 85 grams of potassium iodide in 120 grams of water. The amorphous yellow iodide is thoroughly washed with water and dried over phosphorous pentoxide. Yield: 32.7 grams. (74% of the theoretical yield referred to reacted 5-hydroxy-2,3-diphenyl-l,4-dioxo-tetrahydrophthalazine.)

The iodide is dissolved in 200 cc. of ethyl alcohol of 96% strength and mixed with 50.1 cc; of 0.99206 N- silver nitrate solution (i. e. with the quantity calculated for the iodide content of 19.29% ascertained by analysis). Then the silver iodide is filtered with suction. The filtrate does not contain any silveror iodine ions. The solution is concentrated by lyophilization. The nitrate obtained contains 1 mol of crystal water and decomposes at 150 C. under evolution of gas.

EXAMPLE 10 [2,3-diphenyl-1,4-dioxo-tetrahydrophthalazinyl (5) lfi-dimcthylaminoethyl] -carb0nate-methiodide To a suspension of 35.2 grams of sodium salt of 5- hydroxy-2,3-diphenyl 1,4 dioxo tetrahydrophthalazine (0.1 mol) in 500 cc. of dry methylene chloride there is added, while stirring a suspension of grams of finely triturated chloro formic-acid-(B dimethyl-aminoethyl)- ester-chloromethylate in 250 cc. of dry methylene chloride. After a reaction period of 3 days at room temperature the mass is filtered with suction. The filtrate is concentrated to dryness by evaporation under reduced pressure. The residue is extracted with 120 cc. of water. When filtering withsuction there are recovered from the aqueous suspension a residue of 23 grams of 5-hydroxy-2,3-diphenyl-l,4-dioxo-tetrahydrophthalazine and a clear filtrate, which is submitted to lyophilization. The dry residue is dissolved in 50 cc. of water and precipitated with excess potassium iodide solution of 30%. The sparingly soluble iodide is washed with water and dried in the high vacuum at 56 C. Yield 10 grams (66% of the theoretical yield referred to reacted 5-hydroxy-2,3- diphenyll ,4-dioxo-tetrahydrophthalazine) EXAMPLE 11 6-nicotinoyloxy-2,3-diphenyl-1,4-di0x0- tetrahydroph thalazine 70.4 grams of the sodium compound of 6-hydroxy-2,3- diphenyl-1,4-dioxo-tetrahydrophthalazine (0.2 mol) (obtained according to the directions given in Example 2) in 500 cc. of absolute toluene with 31 grams (0.22 mol) of nicotinic acid chloride are heated under reflux, for 1% hours. Subsequently the hot mass is filtered and cooled. Thereby 56.5 grams of the pure nicotinic acid ester having a melting point of 16917l C. (65.0% of the theoretical yield) crystallize out. Further crystalline fractions can be obtained from the mother liquors.

EXAMPLE 12 5 nicotinoyloxy 2,3 diphenyl 1,4 dioxo tetrahydrophthalazine methiodide (a) A solution of 28.2 grams (0.2 mol) of nicotinic acid chloride in cc. absolute toluene are poured, while stirring, intoa suspension of 70.4 grams of the sodium salt of 5-hydroxy-2,3-diphenyl-1,4-dioxo-tetrae hydrophthalazine (0.2 mol) in 500 cc. of absolute toluene. After a three hours boiling under reflux the hot mass is filtered with suction from the precipitated sodium chloride and concentrated under reduced pressure. 62 grams of the ester having a smelting point of 187-l90 C. crystallize out. By concentrating the mother liquor 10 grams were obtained in addition. Yield: 83% of the theoretical yield.

(b) A mixture of 35.2 grams of the sodium compound of 5 hydroxy 2,3 diphenyl 1,4 dioxo tetrahyrophthalazine, 400 cc. of dry chlorobenzene and 14.1 grams (0.1 mol) of nicotinic acid chlorideare heated for half an hour to 100 C. The hot mass is sucked through a glass filter and concentrated. Yield: 20 grams of ester having a melting point of 184-189 C. (46% of the theoretical yield).

(0) 14.2 grams of nicotinic acid chloride are dissolved in 250 cc. of absolute pyridine. After the reac-, tion heat diminishes 33 grams of 5-hydroxy-2,3-diphenyl-1,4-dioxotetrahydrophthalazine are added to the solution, whereby a temperature rise of 10 C. occurs. The reaction mixture is heated for 1% hours inthe absence of moisture over the steam bath, then evaporated to dryness, and the residue is crystallized from absolute toluene. Yield: 30 grams (69% of the theoretical yield), melting point 185-188 C.

8.05 grams (0.0185 mol) of the nicotinic acid ester obtained according to (a), (b) or (c) are heated together with 2.7 grams (5% of surplus) of methyl iodide and 25 cc. of absolute toluene in the sealed tube for 10 hours to C. After cooling the crystallization product is filtered with suction, boiled out with absolute benzene, again filtered with suction and dried. Yield: 8.7 grams of a crude product (81.5% of the theoretical yield). After the crystallization from hot water the yellow iodide melts at 245-250 C. (with decomposition).

EXAMPLE 13 5 nicotinoyloxy 2,3 diphenyl 1,4 dioxo tetrahydrophthalazine-methyl-methylsulfate 2.9 grams of dimethylsulfate (0.073 mol) are added drop' by drop to a solution of 10 grams of S-nicotinoyloxy 2,3 diphenyl 1,4 dioxo tetrahydrophthalaz'me (0.023 mol), obtained according to the directions given in Example 12, in 500 cc. of absolute xylene, while stirring and at a temperature of 130 C. An immediate turbidity sets in. After stirring for 3 hours at 130 C. the mass is allowed to cool, whereby crystallization sets in. The crystallization product is filtered with suction, washed with absolute benzene and dried at 100 C. under highly reduced pressure. The yield in pure methylsulfate amounts to 9.73 grams (75% of the theoretical yield). Melting point 225-228 C.

EXAMPLE 14 5 nicotinoyloxy 2,3 diphenyl 1,4 dioxo tetrahydrophthalazine-bromoethylate excess ethyl bromide is evaporated and the residue is crystallized from a mixture consisting of absolute alcohol and ether. The salt melts at 240 C. with decomposition. The yield amounts to 2.1 grams (84% of the theoretical yield).

. EXAMPLE l5 5 diethylaminoacetylamino 2,3 diphenyl 1,4 dioxotetrahydroph thalazine 50 grams of-5-amino-2,3diphenyl-1,4-dioxo-tetrahydrophthalazine areslowly heated to 40 C. together with 250 cc. of chloroacetylchloride. When the evolution of hydrogen chloride which, at the beginning, is rather vigorous, has diminished, the chloroacetylchloride in excess is removed under reduced pressure. The residue is dried at 100 C. In a quantitative yield a chloroacetyl derivatives is obtained which melts at 184-187 C. When recrystallized. from acetic acid ethyl ester the melting point'rises toal90=l92.' C. r Y 1 30 grams of this chloroacetyl derivative,(0.0742 mol) are suspended with 80 grams of anhydrous pulverized potassium carbonate in 350 cc. of dry acetone. 9 grams of dry diethylamine (0.123 mol) are added, and the whole is heated for 8 hours under reflux. Subsequently the solvent is distilled off. The residue is taken up with acetic acid ethyl ester and shaken out three times with 100 cc. of 1 N-HCl each time. The combined acid extracts are rendered alkaline by means of sodium carbonate and shaken out with acetic acid ethyl ester. The acetic acid ethyl ester phase washed and dried by means of sodium sulfate after concentration by evaporation results in 25 grams of a pure basic ester melting at 156- 157 C. (76% of the theoretical yield).

EXAMPLE l6 5 -dz'ethylamin0acet0xy-2,3-diph ertyl-I ,4 -dioxotetrahydrophthalazine 102 grams of 5-hydroxy-2,3-diphenyl-1,4-dioxo-tetrahydrophthalazine (0.309 mol) are dissolved in 339 cc. of absolute pyridine and mixed in portions, while' stirring and cooling, with 77 grams of diethylamino-acetylchloride-hydrochloride (0.414 mol). The temperature is not allowed to exceed 28-30 C. After a two hours stirring at room temperature the reaction productstarts crystallizing out. It is then stirred for further 18 hours and vigorously filtered with suction. The crystallization product obtained is freed from pyridine in the desiccator over concentrated sulfuric acid, then dissolved in 1.5 l. of dry methylene chloride, shaken with animal charcoal, filtered and concentrated to about 200 cc. By addition of 500 cc. of absolute ether the hydrochloride precipitates in a crystallized state. In order to be purified it is recrystallized from absolute alcohol. Yield; 62' grams of a decomposition point of 116-118-' C. (with evolution of gas). i

The pyridine mother liquors of the hydrochloride obtained as described above are suitably treated to obtain the basic. ester. The pyridine is evaporated' under reduced pressure, the dark brown residue is taken up with methylene chloride, the whole is shaken with animal charcoal, filtered and extracted in the separation funnel three times with 300cc. of water each time. The aqueous extract is rapidly washed with ether and rendered alkaline by dropwise adding a sodium carbonate solution of 10% strength. The freed basic ester is extracted by a three times shaking out with 250 cc. of ether each time. The combined ether extracts are washed with water, dried by means of sodium sulfate, concentrated by evaporation and recrystallized from a mixture of benzene and petroleum ether. Yield: 19 grams of ester melting at 129-l3l C.'

The mother liquors obtained in the crystallization of the hydrochloride and the basic ester can be further treated in order to obtain 5-hydroxy-2,3-diphenyl-1,4- dioxo-tetrahydrophthalazine. The solvent is removed under reduced pressure, the residueis triturated by means of 500 cc. of water, and the suspension is rendered alkaline by means of sodiumcarbonate solution. The mass having been allowed to stand for 1 hour is acidified bymeans of 2 N-hydrochloric acid and filtered with suction.

' After drying 14 grams of starting material are recovered having a melting'point'of,186 C.-188 C. The total yield of basic ester and its hydrochloride referred to reacted: 5 hydroxy 2,3 diphenyl 1,4 dioxo tetrahydrophthalazine, amounts to 64%.

EXAMPLE 17 5-diethylaminoacetoxy-2,3-diphenyl-1 ,4-dioxotetra-hydrophthalaziiz e-bromo-ethylate 15 grams of S-diethylaminoacetoxy-Z,3-diphenyl-1,4- dioxo-tetrahydrophthalazine (obtained according to the directions given in Example 16) are dissolved in cc. of distilled ethyl-bromide and allowed to stand for 5 days in a sealed v'essel at room temperature. Then the quaternarysalt crystallized out is separated ofi (yield of dry substance 10 grams). The mass is recrystallized from isopropyl alcohol and 7 grams of substance of the decomposition point of 168 C. are obtained (with evolution of gas).

After having been allowed to stand for a prolonged time or when boiled under reflux the ethyl bromidemother liquors yield further crystal fractions of the quaternary salt.

EXAMPLE 18 5-wcrylyloxy-2,3-diphenyl-1,4-dioxotetrahydrophthalazine 8.9 grams of acrylic acid chloride A mol) are added, while stirring, to a suspension of 35.2 grams of the sodium compound of 5 hydroxy-2,3-diphenyl-1,4-dioxo-tetrahydrophthalazinet mol) in 300 cc. of absolute toluene, and the reaction mixture is heated under reflux, while stirring, in the absence of moisture, for 3 hours to 60- 65 C., then filtered with suction from the separated sodium chloride and the mother liquors are concentrated under reduced pressure to cc. On cooling, 26.9 grams of the ester melting at 193 -194 C. crystallize out (70% of the theoretical yield).

EXAMPLE 19 S-stewryloxy-Z,3-diphenyl-1,4-diox0- tetrahydrophthalazine 105.6 grams of the sodium compound of 5-hydroxy-2,3- diphenyl-1,4-dioxo-tetrahydrophthalazine (0.3 mol) are 11 suspended in 700 cc. of dry methylene chloride, while stirring, and mixed with 99.7 grams of stearic acid chloride (0.33 mol). The temperature is raised by 10 CI The mass is heated for two further hours under reflux in the absence of moisture. Then the mass isfiltered with suction from the sodium chloride and concentrated by evaporation until a sirupy consistency is obtained. The residue is boiled out with 2.5 liters of absolute ether. The solution is filtered while being hot, through a glass filter having a suitable width of the pores. While cooling, 71 grams of crystalline stearic acid ester melting at 80-82 C. are separated oft. An opalescent turbidity in the melt disappears only at 90 C. A further 30 grams of the compound having the same melting point can be crystallized from the mother liquors by concentration to 500 cc. Gross yield: 57%.

The substance still contains traces of -hydroxy-2,3- diphenyl-l,4-dioxo-tetrahydrophthalazine which can be separated by repeated crystallization from absolute ether. The substance melts at 80-82 C. for form a completely clear solution. The ester is well soluble in olive oil, oleic acid ethyl ester etc.

EXAMPLE 20 5-0leyloxy-2,3-diphenyl-1,4-diox0 tetrahydrophthalazine 35.2 grams of the sodium compound of 5-hydroXy-2,3- diphenyl-1,4-dioxo-tetrahydrophthalazine (0.1 mol) are suspended, while stirring, in 300 cc. of dry methylene chloride. Then 33 grams of oleic acid chloride (0.11 mol), dissolved in 100 cc. dry methylene chloride, are added, while permanently stirring. The temperature is raised by C. The'mass is heated for 2 hours under refiux and in the absence of moisture, after cooling filtered with suction, and the solvent is removed under reduced pressure. The evaporation residue is vaporized twice under reduced pressure, each time by means of 200 cc. of absolute pseudocumene in order to remove non-reacted oleic acid chloride, as the latter would disadvantageously affect the crystallization of the ester. The residue is crystallized from absolute cyclohexane. There are obtained yellowish, lustrous, semi-solid crystal leaflets which are suitably centrifuged 0E. The mass is first dried on clay, then under highly reduced pressure and 25 grams of oleic acid ester melting at 69 "-70" C. are obtained (42% of the theoretical yield). The purification is carried out better by crystallization from a mixture of methanol and water. In this case the melting point is in the range between 71 and 73 C. The ester is easily soluble in oleic acid ethyl ester as well as in other solvents for fat.

We claim:

1. The compound of the formula 2. The compound of the formula 3. The compound of the formula 4. The compound of the formula 01H; --0 o-oHr-N CaHs . 5. The compound of the formula 6. The process of preparing a 2,3-diphenyl-L4-dioxo' tetrahydrophthalazine of the general formula wherein one R is hydrogen and the other R is hydroxy,

which comprises heating hydrazobenzene with a phthalic anhydride of the general formula l-C O-GHP in the presence of a tertiary organic amine selected from the group consisting of dimethylaniline and pyridine as solvent.

7. A 2,3-diphenyl-1,4-dioxotetrahydrophthalaziue of the general formula I v N R I No references cited. 

7. A 2,3-DIPHENYL-1,4-DIOXOTETRAHYDROPHTHALAZINE OF THE GENERAL FORMULA 